Pharmaceutical companies expend much of their resources in attempts to find new blockbuster drugs (greater than $1 billion/year sales) (D. Eric Walters, BC 5220, Techniques in Biomedical Research, “The Rational Basis of Drug Design”). In order to be successful, a new drug should satisfy several criteria: safe to use; effective for the intended use; stable (chemically and metabolically); good solubility profile; synthetically feasible; and novel (i.e., patentable). An important aspect of drug development is the identification of leads. A lead is any chemical compound that shows the biological activity sought. A lead is not the same as a drug however as it should meet the criteria listed above prior to use as a drug. There are two broad tasks in drug discovery. The first is lead-finding. Here the task is to find a chemical compound that has a desired bioactivity. The second is lead-optimization, modifying the lead structure to build in the other desirable properties (safety, solubility, stability, etc.).
There are many ways to find lead compounds. In the beginning, plants and other natural products were the source of most medicinal substances. As the science of medicinal chemistry evolved, it was discovered that the plants and natural products contained specific compounds that are responsible for the therapeutic effect. It became possible to isolate the active components, so that dosage could be more accurately regulated.
Other medicines came about because of accidental observations and discoveries (e.g., penicillin). The discovery of penicillin led to a large-scale screening effort, in which thousands of soil microorganisms were grown and tested to see whether they could produce other substances that kill bacteria. Antibiotics such as streptomycin, neomycin, gentamicin, erythromycin, and the tetracyclines resulted from these efforts.
Chemical modification of known drugs can often lead to improved drugs. For example, naturally occurring penicillin G is broken down by bacterial beta-lactamases. Addition of two —OCH3 groups produces methicillin, which is resistant to lactamase. Another example of chemical modification is found in the opiate analgesics. The parent compound is morphine, which occurs in opium poppies. Morphine is a powerful analgesic, but it has serious side effects: respiratory depression, constipation, and dependence liability. Thousands of analogs (related chemical structures) have been synthesized in an effort to find analgesics with lower incidence of side effects. In some cases, small changes in chemical structure may have a big influence on the activity. For example, nalorphine is a partial agonist (shows some morphine-like activity, and at higher concentration, antagonizes morphine effects), and naloxone is an antagonist. Considerable simplification of the molecule is possible. For example, meperidine has only two rings instead of four, but it maintains strong analgesic activity. It has better oral absorption than morphine, and shows less GI side effects. Methadone is an analgesic in which the original piperidine ring (6-membered ring containing a nitrogen atom) is completely absent. It retains analgesic activity, has good oral activity, and has a long half-life in the body. Dextromethorphan is constructed on a mirror image of the morphine ring system. It has no opiate analgesic effects or side effects, but is a useful anti-tussive agent.
Some drugs are discovered by observing side effects of existing drugs. For example, minoxidil was found to grow hair on bald men as a side effect in a study of its antihypertensive effects. Viagra's effect on penile dysfunction was discovered in clinical trials for treatment of angina; it had originally been designed as an antihypertensive drug.
In the modern era, most leads are discovered using various screening processes. For example, over a couple of decades, the National Cancer Institute has put hundreds of thousands of different chemical compounds through a battery of anti-cancer assays. Current screening assays often employ miniaturization and automation with robots for high throughput screening, allowing hundreds of thousands of compounds to be screened in a short period of time.
Structure-based molecular design is yet another method to identify lead molecules for drug design. This method is based on the premise that desired drug candidates possess significant structural and chemical complementarity with their target molecules. This design method can create molecules with specific properties that make them conducive for binding to the target site. The molecular structures that are designed by the structure-based design process are meant to interact with biochemical targets, for example, whose three-dimensional structures are known.
Even with the extensive resources expended in drug discovery and design, there are no systematic methods for generating drugs with desired properties. Thus, the art is in need of additional systems and methods to facilitate the discovery and optimization of therapeutic and other useful compounds.